Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†

Abstract

Male contraception is a very active area of research. Several hormonal agents have entered clinical trials, while potential non-hormonal targets have been brought to light more recently and are at earlier stages of development. The general strategy is to target genes along the molecular pathways of sperm production, maturation, or function, and it is predicted that these novel approaches will hopefully lead to more selective male contraceptive compounds with a decreased side effect burden. Protein kinases are known to play a major role in signaling events associated with sperm differentiation and function. In this review, we focus our analysis on the testis-specific serine kinase (TSSK) protein family. We have previously shown that members of the family of TSSKs are postmeiotically expressed in male germ cells and in mature mammalian sperm. The restricted postmeiotic expression of TSSKs as well as the importance of phosphorylation in signaling processes strongly suggests that TSSKs have an important role in germ cell differentiation and/or sperm function. This prediction has been supported by the reported sterile phenotype of the Tssk6 knockout (KO) mice and of the double Tssk1 and Tssk2 KO mice and by the male subfertile phenotype observed in a Tssk4 KO mouse model. Summary Sentence The established role of TSSKs in spermiogenesis and in male fertility, together with their unique kinase features, strongly supports this family of protein kinases as a very promising drug discovery target for development of a non-hormonal male contraceptive.

Expression of the Testis-Specific Serine/Threonine Kinases Suggests Their Role in Spermiogenesis of Bay Scallop Argopecten irradians

“…According to our results, Tssk1/2 distributes in spermatids and spermatozoa of A. irradians, which is in accordance with our assumption of its expression in the late-phase male germ cells based on the qRT-PCR assay. This expression pattern is also similar with that of Tssk1 and Tssk2 in vertebrates (Li et al, 2011;Salicioni et al, 2020), suggesting that the role of Tssk1/2 in spermatogenesis could be conserved in bilaterian animals. Tssk5 of A. irradians possesses the S_TKc domain, in which a conserved serine/threonine protein kinases active site was found.…”

“…According to the qRT-PCR assay and in situ hybridization results, all the five Tssk transcripts displayed the same expression pattern in the scallop testis. The accumulation of Tssks in spermatids or spermatozoa is similar to vertebrates ( Li et al, 2011 ; Salicioni et al, 2020 ), suggesting that the involvement of Tssks in testis development could be conserved across taxa. However, it raises questions such as why it’s necessary to have five Tssks in the scallop and what’s the functional difference between these genes.…”

“…Although we cannot answer yet, studies in mammals may give us some hints. For example, Tssk1 and Tssk4 have an acrosomal and flagellar localization in mouse sperm, while Tssk2 and Tssk6 were present only in a specific sperm head compartment rich in F-actin ( Li et al, 2011 ; Salicioni et al, 2020 ). Difference in subcellular localization of Tssks in mouse suggests that each Tssk member plays a distinct role in sperm function.…”

The Novel Key Genes of Non-obstructive Azoospermia Affect Spermatogenesis: Transcriptomic Analysis Based on RNA-Seq and scRNA-Seq Data

“…Studies have confirmed that TSSK family is expressed after meiosis in male germ cells and mature mammalian sperm. When TSSK family expression is restricted after meiosis, it can affect sperm development through phosphorylation signal transduction ( Wang et al, 2015 , 2016 ; Salicioni et al, 2020 ). Animal experiments have confirmed ( Spiridonov et al, 2005 ) that male mice knocked out of the TSSK6 gene can cause spermatogenesis disorders, including decreased sperm count, decreased motility and survival rate, and increased number of abnormal sperm.…”

De novo Assembly and Analysis of Tissue-Specific Transcriptomes of the Edible Red Sea Urchin Loxechinus albus Using RNA-Seq

“…The testis-specific serine/threonine-protein kinase 3 (TSSK3), centrin 2 (CETN2), cation channel sperm associated 3 (CATSPER3) and sperm surface protein 17 (SPA17) were upregulated specifically in gonad. TSSK3 is a protein involved in the development and maturation of male germ cell [54]. TSSK3 role as a key regulator in spermiogenesis of the Scallop Argopecten irradians has recently been described [55].…”